Dieting periods are common in the history of binge eaters, and cycling between food restriction (FR) and free feeding is a strong predictor of overeating palatable food in response to stress. In past studies, we have observed that chronic FR induces neuroadaptations that increase intracellular signaling and gene expression downstream of D-1 dopamine (DA) receptor stimulation in nucleus accumbens (NAc). Behaviorally, FR subjects display enhanced rewarding effects of DA receptor agonists and psychostimulant drugs, enhanced acquisition of cocaine conditioned place preference, and resistance to extinction of a place preference acquired during a prior ad libitum fed state. In ligt of evidence that drug addiction represents a "hijacking" of the neurocircuitry that mediates appetitively motivated behavior, the enhanced responsiveness to drugs and associated cues during FR likely reflect exploitation of neuroadaptations that normally promote foraging, reward-related learning, and ingestive behavior during periods of food scarcity. Yet, recent developments in Western societies, including prevalent dieting and an abundance of supranormally rewarding energy-dense food, present a set of conditions with potential to ingrain another type of maladaptive behavior, namely, excessive reward-driven feeding. Severe dieting often leads to loss of control and is an established risk factor for binge pathology. The pathogenic role of FR in the development of binge eating has been modeled in laboratory animals by alternating periods of FR with access to palatable food;however, the mechanistic basis of the relationship between FR and binge eating is unknown. In the preliminary data for this project we have shown that administration of a D-1 agonist, or brief intake of 10% sucrose, increase NAc phosphorylation of the glutamatergic AMPA receptor GluA1 subunit on Ser845 with a greater effect in FR than AL rats. Moreover, the enhanced rewarding effect of the D-1 agonist in FR rats was reversed by microinjection of a GluA1 antagonist in NAc shell. Using sucrose, we found that seven consecutive daily 5-min episodes of intake increased GluA1 abundance in the NAc postsynaptic density (PSD), and quantitative electron microscopy revealed an increased intraspinous GluA1 population. Comparing ad libitum fed (AL) and FR rats, it was found that neither FR nor episodic sucrose intake altered levels of GluA1 or GluA2 in the NAc whole cell preparation, suggesting no alteration in synthesis or degradation of these AMPAR subunits. However, sucrose increased GluA1 and GluA2 abundance in the PSD with a greater effect in FR than AL rats. These findings are important because AMPARs mediate enduring forms of synaptic plasticity and behavior modification. Thus, in a recent preliminary study we obtained results consistent with the hypothesis that episodic sucrose intake during FR increases sucrose consumption after AL access to food has been restored. Consequently, the hypothesis to be tested in this project, is that episodic intake of sucrose during FR increases the trafficking of AMPARs to the NAc PSD, and this is the molecular basis of increased sucrose-directed behavior that is expressed when subjects have returned to AL feeding. Experiments of Aim 1 test the prediction that episodic intake of sucrose during FR enhances development of binge-like intake and sucrose-conditioned hyperactivity following restoration of AL feeding. Experiments of Aim 2 test the prediction that episodic intake of sucrose during FR increases AMPAR abundance in NAc PSD in a manner that correlates with behavioral expression of sucrose-directed behavior. Experiments of Aim 3 capitalize on results obtained in Aims 1 and 2 to conduct a representative test of the prediction that interference with AMPAR trafficking during episodic sucrose intake in FR rats prevents future expression of excessive sucrose-directed behavior. By elucidating the synaptic changes induced by food restriction, and investigating their involvement in the acquisition of excessive sucrose-directed behavior, this project has the potential to illuminate risk factors, mechanisms, and novel approaches to preventing and treating binge type eating disorders.
Although a history of severe dieting is a recognized risk factor for binge pathology, there is little or no insight into the mechanistic basis of this relationship. This project is built around our evidence that food restriction alters synapse function in a reward related forebrain region such that episodic breakthrough consumption of highly palatable food may ingrain that behavior and cause an enduring disposition to binge. By elucidating the synaptic changes induced by food restriction, and investigating their involvement in the acquisition of excessive sucrose- directed behavior, this project has the potential to illuminate risk factors, mechanisms, and novel approaches to preventing and treating binge type eating disorders.